The purpose of the work is to determine the mechanism by which cyclic nucleotides affect the growth of malignant cells. The following approaches will be used: 1) We have explored, in a series of rat hepatomas, two of the key enzymes involved in the control of DNA synthesis, thymidylate synthase (TS) and ribonucleotide reductase (RR). We have also examined the level of cyclic nucleotides in these same tumors and found that the TS level is inversely proportional to levels of cyclic AMP while the level of RR is directly proportional to levels of cyclic GMP. This double control of DNA synthesis would explain much of the often difficult to understand data on the control of growth by cyclic AMP and cyclic GMP. We are proposing to determine if cyclic AMP represses TS and cyclic GMP stimulates RR and by what means. 2) We have found that giving HeLa cells cyclic GMP greatly enhances their level of glycogen synthesis. We have found the increase is due to elevation of the enzyme glycogen synthase. We will use this unique system for studying the mode of action of cyclic GMP. BIBLIOGRAPHIC REFERENCE: Goldberg, M.L. Radioimmunoassay for 3', 5'-adenosine cyclic monophosphate and 3',5'-guanosine cyclic monophosphate in human blood, urine, and cerebrospinal fluid. Clin. Chem., March 1977, in press.